sildenafil-citrate and Anxiety-Disorders

Topics: Adolescent; Adult; Ambulatory Care; Antidepressive Agents; Anxiety Disorders; Depressive Disorder; Drug Administration Schedule; Female; Humans; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sexual Dysfunctions, Psychological; Sildenafil Citrate; Sulfones; Treatment Outcome

There are contradictory results about the effects of exercise and sildenafil on cognitive functions.. To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions.. Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6 weeks, 5 days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis.. Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage.

Topics: Acute Disease; Animals; Anxiety Disorders; Cognition; Disease Models, Animal; Exercise Therapy; Exploratory Behavior; Hippocampus; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Physical Conditioning, Animal; Psychotropic Drugs; Random Allocation; Rats, Wistar; Recognition, Psychology; Sildenafil Citrate; Stress, Psychological; Swimming; Treatment Outcome

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolytic-like behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood-brain barrier to elicit central effects.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Carbolines; Disease Models, Animal; Drug Administration Schedule; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Inbred Strains; Sildenafil Citrate; Sulfones; Tadalafil

Topics: Anxiety Disorders; Female; Humans; Orgasm; Paroxetine; Phosphodiesterase Inhibitors; Piperazines; Purines; Selective Serotonin Reuptake Inhibitors; Sex Factors; Sexual Dysfunctions, Psychological; Sildenafil Citrate; Sulfones; Treatment Outcome